Project Summary: Corticostriatal processing of alcohol-paired cues in aversion-resistant drinking (CAPD) Treatment resistant alcoholism is characterized by a loss of control over drinking where individuals persistently use in spite of negative consequences. Currently approved treatments for alcoholism (e.g. disulfiram) aim to reduce drinking by making alcohol consumption aversive. However, this approach is problematic as the hedonic properties of alcohol may no longer motivate drinking behavior in advanced stages of the disease. Rather, when drinking has advanced to a stage that is resistant to aversive consequences, the control of behavior is thought to transition from neural circuits that mediate higher cognitive functions to those that mediate compulsions and habits. Two prominent factors that influence the transition to this stage of drinking are history of alcohol use and genetic risk for alcohol abuse (e.g. family history). Preliminary data from Indiana Alcohol Research Center (IARC) investigators demonstrate that certain rodent models of genetic risk for excessive drinking also tend to quickly form habits and compulsive behaviors. Therefore, a critical need exists to understand how alcohol exposure and genetic factors influence the computational properties of brain regions necessary for the cognitive control of motivated behavior. The long-term goal of this project is to understand the heritable changes in neural computation that facilitate the transition to a loss of control over drinking. Following this transition, alcohol associated cues retain extreme incentive motivational properties even when associated with aversive consequences. A method commonly used to assess aversion resistant drinking (ARD) in rodents is measuring their willingness to consume alcohol adulterated with a bad taste - the quinine devaluation procedure. The central hypothesis of this proposal is that the genetic predisposition to allocate cognitive resources in a stimulus-dependent manner interacts with chronic alcohol use to facilitate ARD. Electrophysiological recordings will be obtained from the medial prefrontal cortex and ventral striatum of awake behaving alcohol preferring (P) and Wistars rats performing a Pavlovian cued access drinking procedure. This approach will allow the representation of alcohol-paired cues to be measured at the individual neuron and ensemble levels to determine how they are processed differently during ARD. Rigorous statistical procedures will be use to quantify the representation of alcohol-paired cues in corticostriatal circuits, and how they are influenced by alcohol history and genetic risk. Aim 1 will examine changes in the representation of alcohol-paired cues following alcohol exposure to determine if drinking history and genetic risk enhances the encoding of alcohol-paired cues in corticostriatal circuits. Aim 2 will determine if drinking history and genetic risk impair the ability of corticostriatal circuits to remap representations of alcohol-paired cues. Finally, Aim 3 will determine if drinking history and genetic risk enhance corticostriatal representations of alcohol-paired cues in Aversion-Resistant Drinking. These data will shed light on the changes in corticostriatal function that underlie ARD, and are therefore consistent with the overarching goals of the IARC.